A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration that pauses myofibers at a neonatal stage. Expression of hypoxia-induced factor 1α (HIF1α), which is induced in the setting of muscle damage, blocks maturation of new myofibers at the neonatal-to-adult fate transition, thereby delaying muscle regeneration. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy and mouse models of CMT type 2A. Pharmacologic and genetic inhibition of HIF1α allowed myofibers to bypass the checkpoint, thereby accelerating muscle maturation. We conclude that skeletal muscle contains a targetable checkpoint that regulates the speed of myofiber maturation.
(Wang et al., Journal of Clinical Investigation, 132 (2022)).